It is known that either the topical application or oral ingestion of certain chemical compounds, known as furocoumarins, certain isomers of which are called psoralens, have an effect on the responsiveness of human skin to sunlight. These psoralen compounds, including 8-methoxypsoralen, which has the generic name of methoxsalen, have long been used in the treatment of certain skin diseases, such as vitiligo, which is characterized by a spotty loss of pigmentation of the skin.
The compound 8-methoxypsoralen having the structural formula ##STR1## and the chemical name 9-methoxy-7H-furo[3,2-g][1]benzopyran-7-one has been obtained from natural sources, namely from the fruit of the Ammi Majus Linn. plant, see, for example, Fabmu et al., "Ammi Majus Linn. Pharmacognostical study and isolation of crystalline constituent, Ammoidin", Quart. J. Pharm. and pharmacol., 21:449, 1948.
Similarly, derivatives of 8-methoxypsoralen (methoxsalen) are known in the literature along with their photobiological activity, see, for example, de Souza et al., J. Hetero. Chem., 3, 42-45, (1966) and Antonello, Gazz. Chim. Ital., 88, 415 (1958).
As used herein, the term "lower alkyl" comprehends straight or branched chain hydrocarbon groups having from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, such methyl, ethyl, propyl, isopropyl and the like. The expression "aryl" denotes an aromatic residue such as phenyl, pyridyl, furyl, or a halo or lower alkyl-substituted phenyl residue such as o-tolyl, m-tolyl, p-tolyl, o-chlorophenyl, p-bromophenyl and the like. By the term "aralkyl" is meant a radical in which a lower alkyl H atom is substituted by an aryl group e.g., benzyl or alkoxy, halo, nitro or alkyl substituted benzyl. By the term alkanol is meant an alcohol of 1 to 7 carbon atom, preferably 1 to 4 carbon atoms, which may be straight or branched chain.
The present invention is drawn to synthetic processes to produce the compound 8-methoxypsoralen and derivatives thereof. The following reaction scheme represents the various alternate process steps and novel intermediates which may be utilized to produce methoxsalen (compound of formula VII) or derivatives thereof. ##STR2## wherein R and R.sub.1 is selected from the group consisting of lower alkyl, aryl or aralkyl, and R.sub.2 is selected from the group consisting of hydrogen, lower alkyl, aryl or aralkyl.